N-{8 (10,11-dihydro-5H-dibenzo{8 a,d{9 cyclohepten-5-yl)methyl{9 amides

ABSTRACT

Octahydrobenzo(6,7)cyclohepta (1,2,3-d,e)pyrido-(or pyrrolo) (2,1-a)isoquinolines, and decahydrobenzo(6,7)-cyclohepta(1,2,3-d, e)azepino(2,1-a)isoquinolines and derivaties thereof, optionally substituted on the pyrrolidine, piperidine or azepine ring. The compounds are useful CNS depressants, anticonvulsant and antiinflammatory agents, and methods for their preparation and use are also disclosed.

United States Patent Bruderlein et al.

[4 1 Oct. 21, 1975 N-[( 10,11-DIHYDRO-5H- DIBENZO[A,DICYCLOHEPTEN-S- YL)METHYL]AMIDES Inventors: Francois T. Bruderlein, Montreal;

Leslie G. Humber, Dollar'd Des Ormeaux, both of Canada Ayerst McKenna and Harrison Ltd., Montreal, Canada Filed: Dec. 21, 1970 Appl. No.: 97,481

Related U.S. Application Data Continuation-impart of Ser. No. 10,306, Feb. 10, 1970, Pat. No. 3,657,250.

Assignee:

U.S. CI 260/562 B; 260/404, 260/343;

260/343.5; 260/343.6; 424/258 lnt. Cl. C07C 103/34 Field of Search 260/570.8, 562

References Cited UNITED STATES PATENTS 3,052,721 9/1962 Bernstein et al 260/562 3,403,157 9/1968 Humber et al 260/570.8

Primary Examinerl-larry I. Moatz Attorney, Agent, or Firm.lohn P. Floyd [57] ABSTRACT 5 Claims, No Drawings N-[( 10.1 l-DIHYDRO-SH- DIBENZO[A,D ]CYCLOI-IEPTEN-- YL)METI-IYL]AMIDES This application is a continuation-in-part of our earlier-filed U.S. Patent application Ser. No. 10,306, filed Feb. 10, 1970, now U.S. Pat. 3,657,250.

BACKGROUND OF THE INVENTION The present invention relates to benzocycloheptaisoquinoline derivatives, to intermediates used in their preparation, and to processes for preparing these compounds.

The benzocycloheptaisoquinoline derivatives of this invention possess valuable pharmacologic properties. For example, the compounds exhibit useful central nervous system depressant, anticonvulsant and antiintlammatory properties. Especially noteworthy are the central nervous system depressant properties of the compounds. More specifically, the benzocycloheptaisoquinoline derivatives of this invention have a more favourable separation of useful central nervous system depressant effects from ataxic properties and undesirable autonomic nervous system effects that are possessed by most other such depressants. In addition, the benzocycloheptaisoquinoline derivatives possess a low order of toxicity.

The combination of attributes stated above renders the benzocycloheptaisoquinolines.of this invention useful and desirable as therapeutic agents.

SUMMARY OF THE INVENTION The benzocycloheptaisoquinoline derivatives of this invention may be represented by formula I,

in which R represents a hydrogen or a lower alkyl and Alk represents the organic radicals designated A, B, C, and D, respectively, in which R 3 4 a 0 1 8 9 10 11 12 13 14 is and R are the same or different selected from the group consisting of hydrogen and lower alkyl with the proviso that the carbon atom to which R and R or R' and R are attached is bonded to the nitrogen atom of formula I, L represents a hydroxyl or an esterified hydroxyl in which the ester forming group is an aliphatic acid containing 2-10 carbon atoms, and M is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, a cycloalkyl containing 3-6 carbon atoms which may be optionally substituted with a lower alkyl, or a phenyl.

DETAILS OF THE INVENTION The benzocycloheptaisoquinoline derivatives of formula I are capable of forming acid addition salts with pharmaceutically acceptable acids. Such acid addition salts are included within the scope of this invention.

The acid addition salts are prepared by reacting the base form of the benzocycloheptaisoquinoline derivative with either one equivalent or preferably an excess of the appropriate acid in an organic solvent, such as ether or an ethanol-ether mixture. These salts, when administered to mammals, possess the same pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the base compounds. Among the acid addition salts suitable for this purpose are salts such as the sulfate, phosphate, lactate, tartrate, maleate, citrate and hydrochloride. Both the base compounds and the above acid addition salts have the distinct advantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of the compounds of formula I which result from asymmetric centers, contained therein. These isomeric forms may be prepared by different methods and are purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractional crystallization of the diastereoisomeric salts formed thereof, for instance, with dor l-tartaric acid or D-(+)-a-bromocamphor sulfonic acid, are also included.

The useful central nervous system depressant activity and the anticonvulsant activity of the benzocycloheptaisoquinoline derivatives of formula I and their acid addition salts with pharmaceutically acceptable acids may be demonstrated in standard pharmacologic tests, such as, for example, the tests described by RA. Turner in Screening Methods in Pharmacology, Academic Press, New York and London, 1965, pp. 69-99 and 164-172, respectively.

When the benzocycloheptaisoquinoline derivatives of this invention are used as central nervous system depressants or anticonvulsant agents in warm-blooded mammals, e.g. rats and mice, they may be used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. in general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 1.0 mg to about 500 mg per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about mg to about 100 mg per kilo per day is most desirably employed in order to achieve effective results.

The benzocycloheptaisoquinoline derivatives of this invention possess another useful pharmacologic prop- CH NH erty; that is, they are useful as antiinflammatory agents. More particularly, the said compounds of this invention exhibit antiinflammatory activity in standard pharmacologic tests, for example, the tests similar to those described by Robert A. Turner in Screening Methods in Pharmacology, Academic Press, pp. 152l63, 1965, based on the reduction of pedal inflammation.

When the benzocycloheptaisoquinoline derivatives of this invention are employed as antiinflammatory agents in warm-blooded animals, e.g., rats, they may be administered orally, alone or in tablets combined with pharmacologically acceptable excipients, such as starch, milk sugar and so forth. They may also be administered orally in the form of solutions in suitable vehicles such as vegetable oils.

The dosage of the benzocycloheptaisoquinoline derivatives of this invention will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords protective effects without any deleterious side effects.

These effective concentration levels are usually ob- I tained within a therapeutic range of 10 mg to mg per kilo per day, with a preferred range of 25 mg to 50 mg per kilo per day.

For the preparation of the benzocycloheptaisoquinolines of formula I, in which Alk represents organic radical A, B or C, we have found it convenient to use the process illustrated by figure 1 in which R is as defined above, Alk is organic radical A, B or C, Y represents the hydroxyl group or chlorine, bromine or iodine and X represents the nucleophilic residue derived from a condensing agent used in the Bischler-Napieralski reaction such as a bromine or chlorine or a phosphate.

FIGURE 1 (Alk organic radicaly A, B or C) III In practising the above process, 10,1l-dihydro-5H- dibenzo[a,d]cycloheptene-S-methylamine (II), described by L. G. Humber et al., J. Heterocyclic Chem. 3, 247 (1966), is condensed with an appropriate lactone of general formula in which Alk is organic radical A, B or C, as defined above, to yield the corresponding hydroxyamide of formula Ill in which Y is the hydroxyl group. The appropriate lactones utilized in this condensation are either available commercially for example, butyrolactone, S-valerolactone, or a-methyl-y-butyrolactone, or they are described with a variety of methods for their preparation in organic chemistry textbooks; such as the textbook, Methoden der Organischen Chemie, Houben- Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561-852.

Convenient conditions for this condensation include heating the dibenzocycloheptenemethylamine of formula II and the appropriate lactone together at a temperature from 100 to 180C for a period ranging from two to 24 hours.

Although the condensation may be accomplished without the use of solvent, the use of an inert solvent, such as an aromatic hydrocarbon, for example, benzene, or a lower alkanol, for example ethanol, is preferred. When this condensation is performed in a solvent, then it is preferable to conduct the reaction at the boiling point of the reaction mixture for a period of seven to 24 hours.

The corresponding hydroxyamide of formula III in which Y is the hydroxyl group, thus obtained, is subjected to the conditions of the Bischler-Napieralski reaction, see for example, W. M. Whaley and T. R. Govindachari in Organic Reactions, 6, 74 (1951). Subsequent heating of the crude product from this reaction in an inert solvent, preferably benzene, promotes the completion of the conversion to the quaternary salt of formula IV in which Alk is organic A, B or C and X is defined as above. Preferred reaction conditions for the Bischler-Napieralski reaction include the use of phosphorus oxychloride as the condensing agent, temperatures ranging from 50 to 150C, a reaction time of one to four hours and the use of toluene or benzene as solvent.

Reduction of the quaternary salt of formula IV, obtained as described above, with either an alkali metal borohydride, in inert solvents such as, for instance, methanol or water, or by means of catalytically activated hydrogen, using preferably Raney nickel or palladium or platinum catalyst, in solvents such as, for example, ethanol, acetic acid or tetrahydrofuran, affords one isomer of the compounds of formula I in which Alk is organic radical A, B or C and R represents a hydrogen atom. For convenience, this isomer is designated as isomer B and is one of the configurational isomers, discussed above.

On the other hand reduction of the quaternary salts of formula IV in the presence of a metal, for example, zinc, with an acid, for example, hydrochloric acid, using an appropriate solvent such as ethanol, affords another isomer of the compounds of formula I in which Alk is organic radical A, B or C and R represents a hydrogen atom. For convenience, this isomer is designated as isomer A.

Hence, this present designation of A and B isomers to compounds in this application is used to distinguish between those stereochemical isomers having different asymmetric centers at the junction of the two rings having the nitrogen atom in common.

Furthermore, it is possible to convert either of the isomers A or B of formula I, in which Alk is organic radical A, B or C and R represents a hydrogen atom, into the other. This interconversion is effected by oxidizing either of the above isomers A and B with mercuric acetate or lead tetraacetate, preferably the former,

followed by treatment with an appropriate acid of formula HX in which X is as defined above, to regenerate the corresponding quaternary salt of formula IV described above. Subsequent reduction of said quaternary salt, according to a method, described above, for

affording the isomer different from the one originally oxidized, completes the interconversion.

We would add that the definition of X, and in turn the definition of the acid, HX, used in the above de- 5 scription of the interconversion of one isomer to the other, may be broadened to include any nucleophilic residue derived from an acid, for example, perchloric acid or lactic acid, capable of forming a quaternary salt of the class represented by formula IV. Such quaternary salts, such as, for example, quaternary salts of formula IV in which X represents a perchlorate or lactate, are then reduced in the aforementioned manner to give the desired other isomer.

In a variation of the process described above,

- II- III IV* I, the starting material of formula II is condensed with an appropriate w-haloalkanoic acid halide of formula ZAlk-COZ in which Alk is organic radical A, B or C and Z and Z are the same or different and each represent chlorine, bromine or iodine to yield the corresponding haloamide of formula III in which Y IS a chlorine, bromine or iodine. This condensation is achieved according to the same conditions employed above for the co'nversion of the starting material of formula II to the hydroxyamide of formula III in which Y is the hydroxyl group except that an excess, preferably a three to five molar excess, of a neutralizing agent, for instance, sodium carbonate, is employed to combine with the acid formed as a byproduct during the reaction.

The haloamide of formula III thus obtained is then subjected to the conditions of the Bischler-Napieralski reaction, described above, to afford the quaternary salt of formula IV which is reduced to compounds of formula I in which R is hydrogen and Alk is organic radical A, B or C according to methods described above.

The appropriate whaloalkanoic acid halides used in the preceding process are prepared from their corresponding acids by treatment with thionyl chloride, thionyl bromide or phosphorus triiodide. The corresponding w-haloalkanoic acids are either commercially available or are described with a variety of methods for their preparation in organic chemistry textbooks, for instance, see description by M. F. Ansell and R. H. Gigg in Rodds Chemistry of Carbon Compounds, Vol. I, part C, S. Coffey, Ed, 2nd. Ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 201-214.

Alternatively, the above w-haloalkanoic acid halides in which Z and Z, are the same may be readily prepared by treating the lactones of general formula in which Alk is organic radical A, B or C with thionyl chloride, thionyl bromide or phosphorus triiodide according to the methods such as described in Methoden der Organischen Chemie", Houben-Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 56l-852 Also, the practise of the present process and its variation (see Figure 1, II III IV I) includes the preparation of the benzocycloheptaisoquinolines of formula I in which Alk is organic radical A, B or C and R represents a lower alkyl. The latter compounds are obtained by the action of a lower alkyl magnesium halide on the corresponding quaternary salt of formula IV according to the conditions generally used for the 3,914,305 7 8 Grignard reaction. For a description of these condi- Methoden der Organischen Chemie, Houben-Weyl, tions, see L. Fieser and M. Fieser, Advanced Organic E. Muller, Ed., Vol. XI/2, Georg Thieme Verlag, Stutt- Chemistry", Reinhold Publishing Corp., New York, gart, 1958, pp. 269-509.

1961, p. 270. Preferred conditions for this reaction in- Accordingly, the alternate preparation of the quaterclude a temperature range from room temperature to nary salt of formula IV, in which Alk and X are as dethe boiling point of the mixture, a reaction time from fined above, from another starting material constitutes 30 minutes to four hours and the use of ether or tetraan alternative process for the preparation of the benhydrofuran as solvent. zocycloheptaisoquinolines of formula 1, which may be Alternatively. the quaternary salt of formula IV in represented schematically by figure 2 in which R, Alk

which Alk is organic radical A, B or C may be prepared 10 and X are as defined above.

' Alk v. Q

by an entirely different process. In this case starting Figure 2 (Alk organic radical A, B or C) material is 10,1l-dihydro-5H- dibenzo[a,d]cycloheptene-S-carboxaldehyde (V) The benzocycloheptaisoquinoline derivatives of forwhich is readily obtained by the action of the Grignard mula 1 of this invention in which R is hydrogen or reagent prepared from chloromethyl methyl ether and lower alkyl and Alk is organic radical D may be premagnesium, on 10,1l-dihydro-5H-dibenzo[a,d]cypared by the process illustrated by figure 3 in which clohepten-S-one, described by S. O. Winthrop et al., J. R R, R, R and R are as defined in the first in- Org. Chem., 27, 230 (1962). Reductive alkylation of stance.

10,1l-dihydro-5H-dibenzo[a,d]cycloheptene-5- l (R H or lower alkyl and Alk organic radical D) carboxaldehyde with an appropriate aminoester of general formula NH Alk-COOR" in which Alk is or- FIGURE 3 ganic radical A, B or C and R is a lower alkyl, accord- This process is based in part on the synthesis of 1 ,2,3- ing to the methods described by A. R. Surrey and H. F. ,4,6,6a,lO,1 l,15bt h d -5H-be [6,7] cyclohep- H mm Am- Chem- 506-, 2127 Or ta[l,2,3-de]pyrido[2,l-a]isoquinolin-5-one (VIII, R Skita and W. Stichmer, German Patent No. 716,668 R, R, R and R H) described previously by L. G. (Chem. Abstr., 38, 2345, 1944) for the preparation of H b r C J, Ch 46, 2981 (1968) and by derivatives of p-aminobenzoic acid, yields the cyclic L. G. Humber and M. A. Davis, US. Patent No.

amide V1. Treatment of the latter compound according 3,361,751, issued Jan 2, 1968. to the conditions of the Bischler-Napieralski reaction, In practising the process represented by figure 3, an described above, affords the desired quaternary salt of acid addition salt, preferably the hydrochloric acid adformula IV in which Alk and X are as described above. dition salt, of 1,7,8,l2btetrahydrobenzo[1,2]cy- The appropriate aminoesters used in the preceding clohepta[3,4,5-d,e]isoquinoline (V11), described by L.

process are prepared by the usual esterification proce- G. Humber et aL, J. Heterocyclic Chem., 3, 247

dures, of their corresponding free acids, see for exam- (1966), is allowed to react with an unsaturated ketone ple, L. Fieser and M. Fieser, Cited above, pp. 370-380. of general formula The corresponding free acids are either available commercially, for example, 4-aminobutyric acid, 5-

aminovaleric acid or o-aminocaproic acid or are de- R"R'C=CR"CCHR' R* scribed with a variety of methods for their preparation in organic chemistry textbooks, such as the textbook, in which R", R, R, R and R are as defined in the first instance. to yield the aminoketone of formula VIII in which R", R, R, R and R are as defined in the first instance. This extremely facile reaction may be performed in an inert solvent such as ethanol; however, when using the lower-molecular weight unsaturated ketones, such as methyl vinyl ketone or ethyl vinyl ketone, it is equally convenient to employ an excess of the unsaturated ketone as solvent for the reaction. Generally, this reaction is performed by heating the components together with or without an inert solvent for prolonged period of time. Preferred conditions for this reaction include heating the mixture on a steam bath from 30 minutes to four hours.

Most of the unsaturated ketones used in the preceding reaction are available commercially; the remainder are described or may be prepared by general methods cited in organic chemistry textbooks and publications, see for example, Rodd's Chemistry of the Carbon Compounds", Vol. I, part C, S. Coffey, Ed., 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 81-91 or D. Beke and c. Szantay, Chem. Ber., 95, 2132 (1962).

If desired, the aminoketone of formula VIII may be separated into the A and B isomers by chromatography and purified by recrystallization.

The aminoketone of general formula VIII may be converted to the benzocycloheptaisoquinoline derivatives of this invention in which R is hydrogen or lower alkyl and Alk is organic radical D by several methods. Among the preferred methods is the procedure whereby the aminoketone is allowed to react with a lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl containing 3-6 carbon atoms which may be optionally substituted with a lower alkyl, or phenyl magnesium halide according to the conditions of the Grignard reaction, cited above. In this manner, there are obtained the compounds of formula I in which R is hydyrogen and Alk is organic radical D wherein R R, R, R and R are as defined in the first instance, L is a hydroxyl and M is other than hydrogen as defined in the first instance (in those compounds where M represents tionally substituted with a lower alkyl, said lower alkyl substituent is preferably located at the position 1 of the cycloalkyl). The latter compounds may be readily converted to their corresponding derivatives of formula I in which R is a lower alkyl by oxidizing said latter compounds with mercuric acetate or lead tetracetate, followed by acid treatment according to the first two steps of the procedure described above for converting either of the isomers A or B of formula I into each other, and treating the resulting, corresponding quaternary salt of formula IV with a lower alkyl magnesium halide according to the conditions of the Grignard reaction, cited above.

Alternatively, the aminoketone of formula VIII may be reacted with appropriate lower akyl lithium derivatives; cycloalkyl lithium derivatives, containing 3-6 carbons, which may be optionally substituted with a lower alkyl; vinyl lithium; allyl lithium; methallyl lithium; lithium acetylide; l-propynl lithium; 2-propynyl lithium; or phenyl lithium; in an inert solvent by essentially the same technique employed in the Grignard reaction. In this manner, the said aminoketones are converted to compounds of formula I in which R is hydrogen and Alk is organic radical D in which R", R, R, R and R are as defined in the first instance, L is a hydroxyl and M is lower alkyl, cycloalkyl containing 3-6 carbon atoms which may be optionally substituted with a lower alkyl; vinyl, allyl, methallyl, ethynyl. I- propynyl, 2-propynyl or phenyl, respectively.

It should be noted that the present conversion of aminoketones of formula VIII to the above compounds of formula I may be effected by the addition of other organoalkali metal reagents. For example, sodium or potassium acetylide may replace lithium acetylide. However, this use of other organoalkali metal reagents is most suitable for preparing compounds of formula I in which Alk is organic radical D in which M is a lower 1- alkynyl.

Furthermore, the compounds of formula I in which Alk is organic radical D in which M is lower alkenyl or alkynyl are readily reduced with hydrogen in the presence of a catalyst to their corresponding lower alkyl derivatives.

Alternatively, the aminoketone of formula VIII may be treated with a reducing agent, such as an alkali metal borohydride or lithium aluminum hydride, to yield the corresponding compound of formula I in which Alk is organic radical D, wherein L is hydroxyl and M is hydrogen, viz., the 5-alcohol described below.

The esterified derivatives of the compounds of formula I in which R is hydrogen or lower alkyl and Alk is organic radical D wherein L is an esterified hydroxyl in which the ester forming group is an aliphatic acid containing 2-10 carbon atoms, are obtained by treating the corresponding compounds in which L is a hydroxyl, prepared as described above, with the appropriate acid anhydride, at temperatures ranging from 0 C, from 6 48 hours, in the presence of sodium acetate.

In another aspect of this invention the aminoketone of general formula VIII may be used conveniently to prepare those benzocycloheptaisoquinolines of this invention of formula I in which R is hydrogen and Alk is organic radical B in which R R, R, R and R are is defined in the first instance, R and R" are hydrogen and R is either a hydrogen or a lower alkyl. In other words, the carbonyl of the aminoketone of general formula VIII may either be reduced to a methylene, or a lower alkyl group may be introduced at the carbonyl site of the aminoketone.

In the first case, where the carbonyl of the aminoketone is reduced to a methylene group, several methods may be employed. These methods include both one step reduction, such as the Clemrnensen reduction or the Wolff-l ishner reduction, or reduction through a reducible intermediate such as, for instance, the corresponding derivative of the aminoketone of formula VIII having a thioketal or tosyloxy group in place of the carbonyl group. Said derivative having the tosyloxy group is obtained by reduction of the corresponding aminoketone of formula VIII, preferably with sodium borohydride or lithium aluminum hydride, followed by tosylation of the resulting corresponding 5-alcohol of formula I in which R is hydrogen, and Alk is organic radical D wherein R R are as defined in the first instance, L is hydroxyl, and M is hydrogen. Said lastnamed 5-alcohol is obtained in two isomeric forms. For a general description of these methods refer to O. H. Wheeler in The Chemistry of the Carbonyl Group, S. Patai, Ed., Interscience Publishers, London, I966, pp. 507-566. In practice we have found that an especially convenient manner for reducing the carbonyl group to the methylene group is to convert the aminoketone of formula VIII to its corresponding thioketal derivative with ethanedithiol and an acid catalyst, for example, boron trifluoride etherate. The resulting thioketal derivative is then reduced with Raney nickel to the desired benzocycloheptaisoquinoline derivative of this invention of formula I in which R is hydrogen and Alk is organic radical B in which R R", R, R and R are hydrogen or lower alkyl and R R and R are hydrogen.

In the second case where a lower alkyl is introduced at the carbonyl site of the aminoketone of general formula VIII, the aminoketone is allowed to react with a lower alkyl magnesium halide or lower alkyl lithium derivative as described above, followed by dehydration of the resulting tertiary carbinol with an acid catalyst, for example, p toluenesulfonic acid, and then catalytic hydrogenation, using the conditions described above, to yield the desired benzocycloheptaisoquinoline of formula I.

Alternatively, the alkyl group may be introduced at the site of the carbonyl group of the aminoketone of formula VIII, by reacting the aminoketone with a lower alkylidenephosphorane according to the conditions of the Wittig reaction, see A. Maercker, Organic Reactions, 14, 270 (1965), followed by catalytic reduction of the resulting alkylidene derivative.

Thus in this second case, there are obtained the hen zocycloheptaisoquinolines of the invention of formula I in which R is hydrogen and Alk is organic radical B in which R, R, R, R and R are hydrogen or lowet alkyl and R and R are hydrogen.

The following Examples will illustrate further this invention.

EXAMPLE 1 a.a-dimethyl-, B,,B-dimethylor y,-y-dimethyl'ybutyrolactone,

a,a-diethyl-, B,B-diethylor 'y,'y-diethyl-'ybutyrolactone,

a,a,-dipropyl-, B,B-dipropy1- or 'y,'y-dipropyl-'ybutyrolactone,

a,,B-dimethyl-, a,-y-dimethylor B,'y-dimethyl-'ybutyrolactone, a-methyl-B-ethyl-, a-ethyl-B-propylor B-propyI-ymethyl-y-butyrolactone, a,B,'y-trimethyl-, a-methyl-B-ethyl-y-propyl, a,a,B,y-tetramethyl-, a,a-dimethyl-B-ethyl-y-propyl, a,a,y-trimethyl-B,B-diethylor a,a,B,B,-y-pentamethyl-y-propyky-butyrolactone, or S-valerolactone,

a-methy1-, B-methyL, 'y-methylor 8-methyl-8- valerolactone,

a-ethyl-, B-ethyl-, 'y-ethy1-, or 8-ethy1-5- valerolactone,

a-propyl-, B-propyL, 'y-propylor 8-propyl-8- valerolactone, a,a-dimethyI-, B,B-dimethyl-, 8,S-dimethyl-8-valerolactone.

'y,y-dimethylor a,8-dimethylor a-ethyl-B-methyL, or a-propyI-8-methyl-5- valerolactone, a,B,'y-trimethylor a,B-dimethyl--y.-propyl-8- valerolactone,

a,B,'y,8-tetramethyl-, (1,13, !,8-tetraethyl-8-methyl-,

e-caprolactone, a-methyl-, B-methyb, 'y-methyl-,

S-methyl or e-methyl-e-caprolactone,

a,a-dimethyl-, a-y-diethyl-a-propyl-e-methyl-,

a,a,B.B,y, y-hexamethylor a,a,B,B,'y,'y,e-heptamethyl-e-ethyI-e-caprolactone instead of 'y-butyrolactone,

N-[( 10,1 1-dihydro-5II-dibenzo[a,d]cyclohepten-5- yl)methyl]-4-hydr0xy-2-methylbutyramide, -4-hydroxy-3-methylbutyramide, -4-hydroxyvaleramide, m.p. 1l2-113C.,

-4-hydroxy-2-ethylbutyramide,

ethylbutyramide,

-4-hydroxy-caproamide,

propylbutyramide,

-4-hydroxy-3-propylbutyramide,

heptanamide,

-4-hydroxy-2,Z-dimethyIbutyramide,

-4-hydroxy-3,3-dimethylbutyramide,

-4-hydr0xy-4-methylvaleramide,

-4-hydroxy-2,Z-diethyIbutyramide,

-4-hydroxy-3,3-diethylbutyramide,

-4hydroxy-4-ethylcaproamide,

-4-hydroxy-2,2-dipropylbutyramide,

-4-hydroxy-3,3-dipropylbutyramide,

-4-hydroxy-4-propylheptanamide,

-4-hydroxy-2,3-dimethy1butyramide,

-4-hydroxy-2,4-dimethylbutyramide,

-4-hydroxy-3-methylvaleramide,

-4-hydroxy-2-methy1-3-ethylbutyramide,

-4-hydroxy-2-ethy1-3-propylbutyramide,

-4-hydroxy-2-propylvaleramide.

-4-hydroxy-2,3-dimethylvaleramide,

-4-hydroxy-2-methyl-3-ethylheptanamide,

-4-hydroxy-2,2,3-trimethylvaleramide,

-4-hydroxy-2,2-dimethyl-3-ethylheptanamide,

-4-hydroxy-2.2-dimethyl-3,3-diethylvaleramide,

-4-hydroxy-2,2,3,3,4-pentamethylheptanamide,

-5-hydroxyvaleramide, mp. 102C, -5-hydroxy-2-methylvaleramide,

S-hydroxy-3-methylvaleramide,

-5-hydroxy-5-methylvaleramide,

-5-hydroxycaproamide,

-5-hydroxy-Z-ethylvaleramide,

valeramide,

-5-hydroxy-4-ethylvaleramide,

heptanamide,

-5-hydroxy-2-propylvaleramide,

-4-hydr0xy-3- -4*hydroxy-2- -4-hydroxy- -5-hydroxy- 5-hydroxy-3-propylvaleramide, -5-hydroxy-4-propylvaleramide, -5 -hydroxyoctanamide, -5-hydroxy2,2-dimethylvaleramide, -5 -hydroxy-3 ,3-dimethylvaleramide, -5-hydroxy-4,4-dimethylvaleramide, -5-hydroxy-5-methylcaproamide, -5-hydroxy-2,2-diethylvaleramide,

-5 -hydroxy-3-ethyl- -5-hydroxy-3,3-diethylvaleramide, -5 -hydroxy-4,4-diethylvaleramide, -5-hydroxy-5ethylheptanamide, -5-hydroxy-2,3-dimethylvaleramide, -5-hydroxy-2,4-dimethylvaleramide, -5 -hydroxy-2-methylcaproamide, -5-hydroxy-3,4-dimethylvaleramide, -5-hydroxy-2,3-diethylvaleramide, -5-hydroxy-2,4-diethylvaleramide, -5-hydroxy-2-propy1octanamide, -5-hydroxy-3 ,4-dipropylvaleramide, -5-hydroxy-2-ethyl-3-methylva1eramide, -5hydroxy-2-propylcaproamide, -5-hydroxy-2,3,4-trimethylvaleramide, -5-hydroxy-2,3-dimethyloctanamide, -5-hydroxy-2,3,4-trimethylcaproamide, -5-hydroxy-2,3-diethyl-4,4-diethylcaproamide, -5 -hydroxy-2,2,3 ,3,4,4-hexamethylvaleramide, -5-hydroxy-2,2,3,3,4,4-hexamethylcaproamide, -5 -hydroxy-2,2,3,3,4,4,S-heptamethylcaproamide, -6-hydroxycaproamide, -6-hydr0xy-2-methylcaproamide, -6-hydroxy-3-methylcaproamide, -6-hydroxy-4-methylcaproamide, -6-hydroxy-5-methylcaproamide, -6-hydr0xy-heptanamide, -6-hydroxy-2,Z-dimethylcaproamide, -6-hydroxy-2,4-diethyl-Z-propylheptanamide, -6-hydroxy-2,4,S-triethyloctanamide, -6-hydr0xy-2-propyl-3 ,5-diethyl-4- methyloctanamide,

-6-hydroxy-2,2,3,3,4,4-hexamethylcaproamide and -6-hydroxy-2,2,3 ,3,4,4,5heptamethyloctanamide,

are obtained.

EXAMPLE 2 To a solution of N-[(10,11-dihydro-5I-I- dibenzo[a,d]cyclohepten-5 yl)methyI]-- -5-hydroxyvaleramide (24.0 g), prepared as described in Example 1, in 400 ml. of toluene is added phosphorous oxychloride (150 ml) and the reaction mixture is refluxed for three hours. After cooling, dilution with petroleum ether precipitates an oil. The supernatant layer is decanted and the residual oil is dissolved in benzene. The benzene solution is washed with water, 10% sodium hydroxide solution and then water again, dried and subjected to reflux for 40 minutes to complete the quaternary salt formation. The resulting precipitate is recrystallized from acetone to give 1,3,45,6- ,10,11,15b-octahydrobenzo[6,7]cyclohepta[1,2,3- de]pyrido[2,1-a]isoquinolinium chloride (IV, Alk CI-I CI-I CH CH and X Cl), m.p. 205207C.

The procedure of Example 2 may be followed to make other quaternary salts of formula IV. Examples of such quaternary salts are listed in Tables I, II and III. In each of these cases an equivalent amount of the starting material listed is used instead of N-[l0,l1- dihydro-SI-I-dibenzo[a,d]cyclohepten-S-yl)methyl]-5 hydroxyvaleramide used in Example 2. The particular starting materials listed below are described in Example 1.

TABLE 1 EXAMPLE STARTING MATERIAL PRODUCT (FORMULA III IN WHICH [(PREFIX LISTED BELOW} Y OH AND Alk IS I,4,5,9,lO,I4b-HEXAHYDRO- STRUCTURE LISTED 3H-BENZO[6,7]CYCLOHEPTA- BELOW) [1.2,3-de]PYRROLO[2,I-a]- ISOQUINOLINIUM CHLORIDE] 3 CH CH CH= parent quaternary salt,

1,4,5,9,10,14b-hexahydro-3H- benzo[6,7]cyclohepta[1.2,3-delpyrrolo[2,I-a]isoquinolinium chloride. mp. 209C. 4 CH(CH,CH CH S-methyl- 5 CH CI-I(CH; )CH 4-methyl- 6 CH CH CH(CH;) 3-methy1- 7 CH(C I-1 -,CI-I CH S-ethyl- 8 CH CH(C H -,)CH 4-cthyl- 9 CH2CH CHg(CzH 3-ethyl- 10 CH(C H-,)CH,CH 5 propyl- II CH CH(C H )CH= 4 propyll2 CH CI I CH(C H 3-propyll3 C(CHgJgCHgCHz 5,5-dimethyll4 CH,C(CH;)=CH 4.4-dimethyll5 CH,CH C(CH;) 3.3-dimethyll6 C(C H CH CH 5,5-diethyl- 17 CH C(C H CH 4,4-diethyl- I8 CH CH,C(C,H 3.3-diethyl- I9 C(C 1-I,) CH CH, 5,5-dipropyl- 20 CH C(C H CH 4,4-dipropyl- 21 en ct-1 0mm,), 3,3-dipropy1- 22 CH(CH )CH(CH -,)CH 5,4-dimethy1- 23 CI-I(CH;,)CI-I CH(CH;,) 5,3-dimethyl- 24 CH CH(CH )CH(CH 4,3-dimethyl- 25 CH(CI-I; )CI-I(C,H )CH, 5-methyl-4-ethyl- 26 CH(C H )CH(C,H,)CH 5-ethyl-4-propy1- 27 CH CI-1(C H )CH(CH 4-propyI-3-methyl- 5,4,3-trimethyl- 5-methyI-4-cthyl-3-propy1- 5,5.4,3-tetramethyl- 5,5-dimethyl-4-ethyl-3-propy1- 5 ,5,3-trimethyl-4A-diethyl- C(C1-I ,C(CI-I3) C(CH )(C H 5,5,4,4.3-pentamethyl-3-propyl TABLE II EXAMPLE STARTING MATERIAL (FORMULA III IN WHICH Y OH AND Alk IS STRUCTURE LISTED BELOW) PRODUCT [(PREFIX LISTED BELOW)- l.3.4,5,6.l0.l l.l5b-OCTAHYDRO- BENZO[6.7]-CYCLOHEPTA[1.2.3-del- PYRIDO[2.l-alISOQUINOLlNIUM CHLORIDE] EXAMPLE 83 7,7.6,6,5,5 ,3-heptamethyl-3-ethylness. The residue is 60 ,3,4,5,5a,9,l0,14b-

crystallized from hexane to yield To a solution of the quaternary salt, l,4,5,9,10.l4bhexahydro-3H-benzo[6,7 ]cyclophepta[ l ,2,3-de]pyrrolo[2,1-a]isoquinolinium chloride (4.0 g), described in Example 3, in 100 ml of methanol, sodium borohydride (4.0 g) is added portionwise. The reaction mixture is refluxed for one hour. After removal of the solvent the residue is taken up in water and extracted with ether. The ether extract is dried and evaporated to dryoctahydrobenzo[6,7]cyclohepta[ l ,2,3-de]pyrrolo[2,1- a]isoquinoline (Isomer B) (I, R H and Alk CH CH CH m.p. l12l13C. The corresponding hydrochloric acid addition salt of this free base has m.p. 253254C. (recrystallized from acetone).

The above isomer B of Example 83 as well as the corresponding Isomer A, may also be prepared by following the procedure of Example 85, see below, by using an equivalent amount of quaternary salt noted in Example 83 instead of the quaternary salt noted in Example 85. Accordingly, l,3,4,5,5a,9,10,l4b-

octahydrobenzo[6,7]cyclohepta[ l ,2,3-de]pyrrolo[2, i

a]isoquinoline (isomer A), m.p. 76-77C, is obtained. The corresponding hydrochloric acid addition salt of the latter compound has m.p. 226C.

EXAMPLE 84 The quaternary salt, 1,3,4,5,6,10,l 1,15boctohydrbenzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1- a]isoquinolinium chloride (1.3 g), described in Exampie 2, is dissolved in 50 ml. of ethanol and subjected to hydrogenation at room temperature under atmospheric pressure in the presence of platinum oxide (50 mg).

After a reaction time of two hours, the catalyst is removed by filtration and the filtrate is evaporated to dryness. The residue is crystallized from hexane to afford 1,4,5,6,6a,i0,11,15b-octahydro-3H- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,1- a]isoquinoline (isomer B) (I, R H and Alk CH CI-i CH- CH2). mp. 136C. The corresponding hydrochloric acid addition salt of this free base has m.p. 235236C.

EXAMPLE 85 A mixture of the quaternary salt, l,3,4,5,6,l0,l 1,15- b-octahydrobenzo[6,7]cyclohepta[1,2,3- de]pyrido[2,i-a]isoquinolinium chloride (2.0 g) and zinc dust (4.0 g) in 40 ml of concentrated hydrochloric EXAMPLE NUMBER OF EXAMPLE acid and 150 ml of ethanol is heated on a steam bath for one hour. The alcohol is removed by evaporation and the remainder of the mixture is rendered neutral with concentrated ammonia. The mixture is then extracted with benzene. The benzene extract is dried and evaporated to dryness. The residue is subjected to chromatography on 120 g of neutral alumina (activity II). Elution with hexane affords 1,4,5,6,6a,l0,1i,15b' octahydro-3H-benzo[6,7 ]cyclohepta[ l ,2,3-

l0de]pyrido[2,1-a]isoquinoline (isomer B), identical with the product described in Example 84. Subsequent eiution with benzene affords the corresponding isomer A. Recrystallization of this isomer A from hexane affords crystals, m.p. 9092C.

The hydrochloride addition salt of 1,4,5,6,6a,10,l i,- b-octohydro-3H-benzo[6,7]cyclohepta[1,2,3- de]pyrido[2,1-a]isoquinoline (isomer A) has m.p. 255-260C, after recrystallization from acetone.

The procedures of Examples 83, 84 and 85 and the procedure of Example 85 may be followed to prepare the B or A isomers, respectively, of the compounds of formula I noted in those Examples or other benzocycloheptaisoquinoline derivatives of formula I in which R is a hydrogen. in each case an equivalent amount of appropriate starting material, a quaternary salt of formula IV to give the desired product is used in place of the quaternary salts noted in Examples 83, 84 and 85. Examples of such benzocycioheptaisoquinoline deriva tives which may be prepared by these procedures are listed in Tables IV, V and V1 with a notation referring to the source of the appropriate starting material.

TABLE IV PRODUCT DESCRIBING QUATERNARY [(PREFIX LISTED BELOW SALT STARTING MATERIAL I3.4.5.5113,10.14b-OCTAHYDRO- BENZO[6,7ICYCLOHEPTAI1,2,3deI- PYRROLOI2.1-a1ISOQUINOLINE] 3 3 5,5,4,4,3-pentamethyl-3-propyl- TABLE v PRODUCT EXAMPLE NUMBER OF EXAMPLE DESCRIBING QUATERNARY [(PREFIX LISTED BELOW)- SALT STARTING MATERIAL 1.4,5,6,6a,11,15b-OCTAHYDRO- 3H-BENZO[6,7]CYCLOHEPTAI1,2,3-clel- PYRIDO[2,1-a]ISOQUINOLINE] 116 34 6-methyl- 1 17 35 S-methyl- 1 18 36 4-methyl- 1 19 37 3-methyl- 120 38 6-ethyl- 121 39 S-ethyl- 122 40 4-ethyl- 123 41 3-ethyl- I24 42 6-propyl- 125 43 5-propyl- 126 44 4-propyl- 127 45 3-propy1- 128 46 6,6 dimethyl- 129 47 5.5-dimethyl- 130 48 4,4-dimethyl- 131 49 3.3-dimethyl- 132 50 6.6-diethyl- 133 51 5,5-diethyl- 134 52 4,4-diethyl- 135 53 3,3-diethyl- 136 54 6.5-dimethyl- 137 55 6.4-dimethyl- 138 56 6,3-dimethyl- 139 57 5,3-dimethyl- 140 58 6,5-diethyl- 141 5 9 6,4-diethyl- 142 60 6,3-dipropyl- 143 61 6,3-dipropyl- 144 62 6-ethyl-5 -methyl- I45 63 6-propyl-3-methyl- 146 64 6,5,4-trimethyl- I 147 65 6,5-dimethyl-3-propyl- 148 66 6,5,4.3-tetramethyl- I49 67 6,5,4,4-tetraelhyl-3-niethyl- 68 6,6,5 ,5 ,4,4-hexamethyl- 151 69 6,6,5,5,4,4,3-heptamethyl- 152 70 6,6.5,5.4,4,3,3-octamethyl- TABLE VI EXAMPLE NUMBER OF EXAMPLE PRODUCT DESCRIBING QUATERNARY [(PREFIX LISTED BELOW)- SALT STARTING MATERIAL 1.3,4,5,6.7,7a,11,12,16b-DECAHYDRO- BENZO[6,7]CYCLOI-IEPTA[1,2.3-de-l- AZEPINOI 2, 1 -a]ISOQUINOLINE] EXAMPLE To a warm solution of the benzocycloheptaisoquinoline, l,4,5,6,6a,10,1l,l5b-octohydro3H- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,la]isoquinoline (Isomer B) (0.7 g), described in Example 84, in 18 ml of water, 4 ml of acetic acid and 5 m1 of tetrahydrofuran, mercuric acetate (3.08 g) is added portionwise. The mixture is boiled for one hour. Solid mercurous acetate is collected on a filter and the fil' trate is rendered alkaline with 10% aqueous sodium hydroxide and extracted with ether. The ether extract is dried, and then treated with gaseous hydrochloric acid. The resulting precipitate is collected and recrystallized from acetone to afford a product identical to 1,3,4,5,6,- 10,11,15b-octahydrobenzo[6,7]cyclohepta[1,2,3- de]pyrido[2,1-a]isoquinolinium chloride obtained in Example 2.

The same product is isolated when the corresponding lsomer A, described in Example 85, instead of above Isomer B, is used as the starting material. I I

In the same manner, but using any of the benzocycloheptaisoquinolines listed in Examples 83, 86 to 164 and 189 to 292, see below, instead of the benzocycloheptaisoquinoline of this Example, the corresponding quaternary salts of formula IV are obtained.

EXAMPLE 166 bonate (35.0 g) in 250 ml of benzene is stirred and subjected to reflux for 16 hours. The" reaction mixture is diluted with water. The benzene layer is separated and washed with water, dried and evaporated to dryness.

The residue is crystallized from benzene-hexane to afford the haloamide N-[(10,1 l-dihydro-SH- dibenzo[a,d]cyclohepten--y1)methyl]-5-chlorovaleramide (111, Alk Cl-1 Cl-1 C1-1 Cl-1 and Y Cl), m.p., 98-99C.

The procedure of Example 166 may be followed to make other haloamides of this invention of formula III in which Alk is as defined above and Y is a chlorine by using an appropriate w-haloalkanoic acid halide, described above, instead of 5chlorovaleric acid chloride.

The above N-[(10,l1-dihydro-5 H- dibenzo[a,d]cyclohepten-5-yl)methyl]-5-chlorovalera mide, and the other haloamides of this invention may be converted to the corresponding quaternary salts of formula IV of this invention for example, the quaternary salts described in Examples 2 to 82, by subjecting said haloamides to the conditions of the Bischler- Napieralski reaction, for example, the conditions described in the procedure of Example 2.

EXAMPLE 167 A solution of chloromethyl methyl ether (40.2 g, 0.5 mole, freshly distilled) in dry tetrahydrofuran (80 ml) is prepared, and about 5 ml of that solution are added to a stirred mixture of magnesium turnings (12.0 g, 0.5 g atom) and mercuric chloride (500 mg) in tetrahydrofuran (20 ml) until an exothermic reaction ensues. The flask is cooled to 0: and the remainder of the chloromethyl methyl ether solution is added dropwise with thorough agitation. After completion of addition a solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten5-one (56.1 g 0.25 mole) in tetrahydrofuran is added dropwise. The reaction mixture is stirred overnight at room temperature and the complex is hydrolyzed with ice-cold ammonium chloride solution. The aqueous layer is extracted with ether (3 X 100 ml) and the combined extracts are washed with sodium chloride solution, dried and evaporated under reduced pressure to give 10,1 1-dihydro-5-methoxymethyl-5H- dibenzo[a,d]cyclohepten-5-ol as an oil with b.p. 143 144 C/0.05 mm, y f 3500 cm, 2820 cm.

EXAMPLE 168 A solution of 10,1 l-dihydro-5-methoxymethyl-5H- dibenzo[a,d]cyclohepten-5-ol (52.0 g 0.21 mole) and formic acid (60 ml) is heated under refluxing conditions for three hours. The mixture is cooled, diluted with water (500 ml) and the oil is extracted into benzene. Evaporation of the solvent yields the crude aldehyde as a viscous oil.

The product is stirred overnight at room temperature with a solution ofGirard-T reagent (40 g) in methanol (400 ml). The precipitate is combined with the residue obtained on evaporation of the methanol. The Girard adduct is dissolved in water and the solution is extracted with ether (6 X 100 ml) to remove noncarbonylic impurities. Hydrolysis of the adduct is effected by stirring the aqueous solution overnight (25) with 40% sulfuric acid. The precipitated product is filtered off, washed well with water and dried to yield 10,- 1l-dihydro-5H-dibenzo[a,dlcycloheptene-S- carboxaldehyde as a solid with m.p. 76-77C which may be purified by distillation (h.p. 135138C/0.2 0.3 mm) or recrystallization from cyclohexane to m.p. 78C., fff 2700 (C-H stretching); 1720 cm (CHO).

The compound is also characterized as the 2,4-dinitrophenylhydrazone, mp. 217C (from acetic 22 acid) 3300 (NH); 1610 (c=1\1 1315, 1510 cm (N02).

EXAMPLE 169 By subjecting a mixture of 10,11-dihydro-5H- dibenzo[a,dlcycloheptene-S carboxaldehyde (2.2 g), described in Example 168, and S-aminovaleric acid ethyl ester (1.45 g) and zinc dust (3.0 g) in 3.0 ml of acetic acid and ml of benzene, to a two hour reflux, followed by removal of the excess zinc by filtration, addition of dilute sodium hydroxide solution to render the mixture alkaline and extraction with benzene affords the cyclic amide, N-[(10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5-yl)methyl]-2-piperidone, fl'i g 1650 cm, as an oil. Further treatment of this oil according to the conditions of the Bischler- Napieralski reaction described in Example 2, yields a product identical with the quaternary salt, 1,3,4,5,6,10- ,1l,l5b-octahydrobenzo[6,7]cyclohepta[1,2,3 de]pyrido[2,1-a]isoquinolinium chloride obtained in Example 2.

The procedure of Example 169 may be followed to make other quaternary salts of formula IV, for example, the quaternary salts described in Examples 3 to 82. In each case an equivalent amount of the appropriate amino ester ofgeneral formula NH --A1kCOOR", in which Alk is organic radical A,'B or C and R is a lower alkyl, is used instead of S-aminovaleric acid ethyl ester.

EXAMPLE 170 The quaternary salt, 1,3,4,5,6,10,11,15boctahydrobenzo[6,7]cyclohepta[ l ,2,3-de]pyrid0[2, l a]isoquinolinium chloride (0.001 mole), described in Example 2, is added portionwise to the alkyl magnesium halide, methyl magnesium iodide (0.002 mole) in 100 ml of ether. The reaction mixture is refluxed for 40 minutes. Excess methyl magnesium iodide is destroyed by the slow addition of a saturated solution of ammonium chloride. The ether layer is separated, dried and concentrated to dryness. The residue is subjected to chromatography on alumina (activity-l Elution with benzene gives 6a-methyl-1,4,5,6,6a,10,11,15boctahydro-3H-benzo[6,7]cyclohepta[1,2,3- de]pyrido[2,l-a]isoquinoline (1, R CH and Alk CH CH CH CHQ; m.p. 119120C, after recrystallization from hexane. This corresponding hydrochloride acid addition salt of this benzocycloheptaisoquinoline derivative has mp. 270C (dec.) after recrystallization from methanol-ether.

The procedure of Example 170 may be followed to prepare the remaining benzocycloheptaisoquinoline derivatives of this invention of formula I in which R represents a lower alkyl, by using the appropriate quaternary salt of formula IV, for example the quaternary salts described in Examples 2 to 82, and together with the appropriate lower alkyl magnesium halide. For example, in this manner the 6a-methyl-, 6a-ethyl and 6a-propyl analogs of the benzocycloheptaisoquinoline derivatives described in Examples 83 164 are obtained by using the same quaternary salt starting material employed in the those Examples together with the alkyl magnesium halides, methyl, ethyl or propyl magnesium bromide, respectively.

EXAMPLE 171 To freshly distilled 1-buten-3'one (5.4 g), l,7,8,12b-

tctrahydrobenzo[ I .ZIcycIoheptal 3,4,5- delisoquinoline hydrochloride (5.4 g) is added portionwise. The mixture is heated on a steam bath for 30 minutes. becoming homogenous and finally semi-solid. The mixture is diluted with ether and the resulting precipitate is collected on a filter and washed with ether. The precipitate is dissolved in aqueous sodium hydroxide and extracted with ethyl acetate. The extract is dried and evaporated to dryness. The residue is crystallized from acetone-hexane to afford I,3,4,6,6a,10,l I,- b-octahydro-5 H-benzo[6,7 ]cyclohepta[ l ,2,3-de]- pyrido[2,l-a]isoquinolin-5-one, (VIII, R", R, R, R and R H), m.p. l50-I55C. This product is a mixture of the A and B isomers, which may be separated by chromatography on silica gel. Elution with chloroform in benzene gives I,3,4,6,6a,l0,1l,l5boctahydro-5H-benzo[6,7]cyclohepta[1,2,3-de1- pyrido[2.l-a]isoquinolin-5-one (Isomer B), mp. 202- 203"C after recrystallization from acetone-hexane. Elution with chloroform gives the corresponding Isomer A, m.p. l63-l65C, after recrystallization from acetonehexane.

The procedure of Example 171 may be used to prepare other aminoketones of formula VIII. In each case an equivalent amount of an appropriate unsaturated ketone of formula in which R R R, R and R are as defined in the first instance, is used instead of l-buten-3-one. Examples of such aminoketone are listed in Table VII together with the appropriate unsaturated ketone used as starting material.

TABLE VII an oily residue. The residue is purified by chromatography on alumina. Elution with benzene-acetone affords the free base, 5-ethyl-I,4,5,6.6a,l0,l l,l5b-octahydro- 3H-benzo[6.7]cyclohepta[ I ,2.3-de]pyrido[2.la]isoquinolin-5-ol, (Isomer A) (I, R H and Alk )cHg), 'Ym (TI (broad). The corresponding hydrochloric acid addition salt of this product has m.p. 263C (dec.).

In the same manner but using the B isomer instead of the A isomer of l.3,4.6,6a,l0,1I,15b-octahydro-5H- benzo[6,7]cyclohepta[ I ,2,3-de]pyrido-[2,I- a]isoquinolin-5-one, described in Example 171, the B isomer of 5-ethyl-l.4,5.6.6a,l0,l I.I5b-octahydro3H- benzo[6,7]-cyclohepta[ l .2,3-de]pyrido[2,la]isoquinolin-5-ol. nmr (CDCI;,)64.52 (d,lH); the corresponding hydrochloric acid addition salt of this isomer has m.p. 245-249C.

EXAMPLE 190 To 30 ml of a commercial molar solution of the lithium derivative, t-butyllithium, (0.03M) in pentane, 1,3- ,4,6,6a,10,l 1,15b-octahydro-5H- benzo[6,7]cyclohepta[ l ,2,3-de]pyrido[2,la]isoquinolin-5-one (Isomer A) (3.0g.,0.0lM) dissolved in ml. of benenzene is added dropwise with stirring and cooling. After stirring at room temperature for 2.5 hr., the reaction mixture is decomposed with water. The organic layer is separated, dried over magnesium sulfate and concentrated to give an oil. The oil is dissolved in benzene and subjected to chromagraphy on a column of basic alumina (activity II). Elution of the column with chloroform-benzene (I:I) gives S-tbutyl-I ,4,5,6,6a,l0,l 1,15b-octahydro-3H- benzo[6.7]cyclohepta[ I ,2,3-de]pyrido[2, l a]isoquinoIin-5-ol (Isomer A),nmr(CDCl )84.87

STARTING MATERIAL AMINO KETONE PRODUCT (FORMULA VIII) [(Prefix listed below)- I,3,4.6.6a.l0.1 I,lSb-OCTAHYDRO- RI! Rla RH RH R16 I72 CH H H H H B-methyl- 173 H H CH H H 4-methyl- I74 H H H CH H 6-methyl-;(m.p.lIII-183C) I75 C H H H H H 3-ethyl- 177 H H H C H H 6-ethyl- I81 CH CH H H H 3,3-dimcthyl-;(m.p.I-192C) I82 H H H CH CH 6,6dimethyl- I83 H H H C H C H 6,6-diethyl I84 CH H H C H H 6-ethyl3-methyl- I85 CH CH H H nC;H 3,3-dimethyl-6-propyl- I86 CH CH CH CH CH 3.3.4.6.6-pentamethyl- I88 CH H CH H H 3,4-dimethyl-;(m.p.239242C) EXAMPLE 189 A solution ofthe aminoketone, l,3,4,6,6a,10,l I,l5b- 0 (t,1H). This corresponding hydrochloric acid addition salt of this compound has m.p. 305-3I0C.

In the same manner but using the B isomer instead of the A isomer of I,3,4,6,6a,l0,l I,l5b-octahydro-5H- benzo[6,7]cyclohepta[ I,2,3-de]pyrido[2, I a]isoquinolin-5-one, described in Example 171, the B isomer of the product of this Example is obtained.

EXAMPLE 191 A solution of l,3,4,6,6a,l0,11,15b-octahydro-5H- benzo[6,7]cyclohepta[ 1 ,2,3-de]pyrido[2,la]isoquinolin-5one (Isomer A) (3.0g), described in Example 171, in tetrahydrofuran (70 ml) is added dropwise to a suspension of sodium acetylide in-liquid ammonia, prepared from 2.5 g of sodium in 200 ml of ammonia by bubbling acetylene in presence of ferric nitrate as catalyst. The reaction mixture is stirred for 3 hours in a dry ice-acetone bath, then g of ammonium chloride is added and the ammonia is allowed to evaporate at room temperature. Water is added and the residue is extracted with ethyl acetate. The extract is dried over magnesium sulfate, and evaporated to dryness. The residue is crystallized from hexane to give 5- ethynyl-l,4,5,6,6a,l0,l1,15b-octahydro-3I-I- benzo[6,7]ocyclohepta[1,2,3- de]pyrido[2,l-a]isoquinolin-5-ol (isomer A)(I,R= and Alk CH CH C(C II CH)(OH)CH m.p. 165-l66C. The corresponding hydrochloride salt has m.p. 280 -282C.

In the same manner but using the B isomer instead of the A isomer of l,3,4,6,6a,10,11,15b-octahydro-5H- benzo[6,7]cyclohepta[1,2,3- de]pyrido[2,1-a]isoquinolin-5-one, described in Example l71, the B isomer of the product of this Example is obtained, m.p. l76-178C.

An equivalent amount of potassium acetylide, prepared from potassium instead of sodium, and acetylene, as described above, may replace the sodium acetylide in the procedure of this Example.

In the same manner but using the B isomer instead of the A isomer of S-ethynyl-l,4,5,6,6a,10,l1,15boctahydro-3H-benzo[6,7]cyclohepta[1,2,3- de]pyrido[2,l-a]isoquinolin-5-ol, described in Example 191, there is obtained the B isomer of 5-ethyll,4,5,6.6a.l0,l1,15b-octahydro-3H-benzo[6,7]cyclohepta[ l .2,3-de]pyrido[2. l -a]isoquinolin-5-ol, nmr(CDCl )64.52(d,ll-l), which is an isomer of the product of the same name obtained in Example 189 with respect to the configuration of the S-hydroxyl.

The procedure of Examples 189 or 190 may be used to prepare other S-substituted derivatives of 1 .4,5,6,6a- ,l0,l 1,15b-octahydro-3l-I- benzo[6,7]cyclohepta[1,2,3-de]pyrido[d,la]isoquinolin-5-ol, compounds of formula I in which R is hydrogen and Alk is organic radical D in which R R R, R" and R are hydrogen, L is hydroxy and M is as defined in the first instance. An equivalent amount of the appropriate Grignard reagent in the case of the procedure of Example 189, or the appropriate lithium derivative, in the case of the procedure of Example 190, is used, instead of ethyl magnesium iodide or tbutyllithium, respectively. Examples of such S- substituted compounds prepared in this manner, are listed in Table VIII together with the Grignard of lithium derivative that is used in the Example.

TABLE VIII Example Grignard Reagent Product[(Prefix nmr of product, m.p. of corresor Lithium Derilisted below)- '6(CDCI;,) ponding hydrovative, starting 1,4,5,6,6a,10, chloric acid material 11.15b-octahydroaddition salt.

3I-I-benzo[6,7]- cyclohepta[ 1.2.3- de]pyrido[2,l-a]- isoquinolin-S-ol] 193 n-cJ-nu S-butyl- 4.90 (t,lH) 287-289 194 CH =CHCH MgBr S-allyl- 4.70 (t,lH) 280-282 195 (Cl-1:),CHMgCI 5-isopropyl- 4.90 (t,lH) 282-284 196 CH MgCl S-methyl- 4.92 (t,1H) 254-256 197 (ct-1,) HLi 5-cyc1opropyl- 4.92 (t,lH) 260-262 198 CH C I CLi 5-(1-propynyl)- 4.54 (t,ll-I) 199 nC H-,Li S-propyl- 4.87 (t.lH) 290-291 200 nC H, Li 5-hexy1- 4.89 (t,lH) 285-287 201 Q-Li S-phenyl- 4.92 (t,lH) 290-292 202 CH HL' 5- lohex l- 4.92 t,lH 312-314 :ls l y Y 203 CI-I CHLi 5-vinyl- 4.90 (t,1H)

EXAMPLE 192 The corresponding B isomers of the products of Examples 193-203 are obtained in the same manner as the A isomers of these Examples by using the B isomer instead of the A isomer of the starting aminoketone of Example 189.

The procedure of Example 189 may be used to prepare S-ethyl derivatives of formula I in which R is hydrogen and Alk is organic radical D in which R", R R, R' and R are each hydrogen or lower alkyl, L is hydroxy and M is ethyl. Example of such S-ethyl derivatives are listed below in Table IX. In each case an equivalent amount of the corresponding, starting aminoketone, noted by the Example in which it is prepared, is used instead of octahydro-5H-benzo[6,7]cyclohepta[ 1,2,3-de1- pyrido[2,1-a]isoquinolin5-one.

TABLE IX Example No. of the Product [(Prefix nmr of lf rom.p. of corres- Example in which listed below)- duct 8 (CDCI;,) pending hydrostarting aminol,4.5,6,6a.l0,l I, chloric acid ketone is prelSb-octahydroaddition salt,

pared 3H-benzo[6.7]- C cyclohepta[ 1,2- 3-de]pyrido[2,lalisoquinolin-S- ol] 204 I81 -ethyl-3,3-dimcthyl- 4.77(d.l H) 285-286 205 I88 5-ethyl-3.4dimethyI- 4.88(d,IH) 278-282 206 174 5-ethyI-6-methyl- 4.42(d,I H) 2I5-2I8 207 I 87 4-sec-butyI-5-ethyl- 4.57(d,I H)

The procedure of Examples 189 or I90 may be followed to prepare other i-substituted derivatives of formula l in which R is hydrogen and Alk is organic radical D in which R R R, R and R are each hydrogen or lower alkyl, L is hydroxy and M is as defined in the first instance. Examples of such 5-substituted derivatives are listed in Table X together with the appropriate stating aminoketone which is noted by the Example in which the starting aminoketone is prepared. Also, noted therein is the appropriate Grignard reagent, in the case of the use of the procedure of Example I89 or lithium derivative, in the case of the use of the procedure of Example 190, which is used in the Example.

For instance, the product of Example 279, 4-secbutyI-S-isopropyI-I ,4,5,6,6a,l0,l 1,15b-octahydro-3H- benzo[6,7]cyclohepta[ I ,2,3-de]pyrido[2, I a]isoquinolin-5-ol; nmr8(CDCl 5.00(m,IH), is obtained by using the aminoketone of Example I87 and the lithium derivative, isopropyllithium, in the case of using the procedure of Example 190 as described above. The corresponding hydrochloric acid addition salt of this product has m.p. 250256C.

TABLE X EXAMPLE No. of the Grignard reagent or Product [(Prefix listed below)- Example in lithium derivative, I,4,5,6,6a,I0 I l,I5b-octahydrowhich the starting material 3H-benzo[6,7]cyclohepta[1,2,3-

starting de]pyrido[2.l-a]isoquinolinaminoketone 5-oI] is prepared 208 I72 n-C,H,Li S-ethyI-S-methyl- 209 I72 CH,=C(CH,)CH,MgCI 3-methyI-5-(2-methallyl)- 2I0 172 CH C I CLi 3-methyl-5-( I-propynl)- 21 I I72 (CHQiHMgBr 5-cycIobutyl-3-methyll I I 212 I72 (CH C(CH;)L|* 3-methyI-5-( I-methylcyclohexyl)- 213 172 O-Mg Br 3-methyl-5-phenyl- 2 I 4 I7 3 nC H ,MgCI 4-mcthyI-5 -propyl- 2 I 5 I73 CH =CHLi 4-methyl-5-vinyl- 216 I73 HC I CCI-I,Li 4-methyl-5-(2-propynyl)- I" 1 217 I73 (CH HLi 5-cyclopentyl-4-methylh 2 I 8 I73 (CHz) f(C H,-,Li* S-( I-ethylcyclopentyl)-4-methyl- 219 173 O-Mg Br 4 methyI-5-phenyl- 220 174 c1-'1,=cl1c1-1,Li 5-allyI-6-methyl- 221 I74 HC CLi S-ethynyI-G-methyl- 222 I74 (CH HLi S-cyclopropyl-G-methyl- 223 I74 ((EH=),E(CH;, )Li 6-methyl-5-(I-methylcylopropyl)- 224 I 75 t-C H LI 5-t-butyl-3-ethyl- 225 I75 Cl-I,=CHCH,MgBr 5allyl-3-ethyI- 226 I75 HC I CLi 3-ethyI-5-ethynyl- 227 I75 (CH )CHL' 5 I I3 th I 2 z I P p) Y f 228 I 75 (Cl-I C(n-C H-,)Li* 3-ethyl-5-( I-propylcyclobutyl)- 229 OMgBr 3-ethyl-5 phenyl 230 I76 C l-I MgI 4.5-diethyl- 231 I76 CH =C(CH;,)CH,MgCI 4-ethyI-5-(2-methallylJ- 232 I76 HC I CCH Li 4-ethyl-5-( Z-propynyl)- f"'"l 233 I76 (CHz)5 HLI 5-cyclohexyl-4-ethyl- TABLE X Continued EXAMPLE No. of the Grignard reagent or Product [(Prefix listed below)- Example in lithium derivative, 1,4.5.6,6a.10,1 1,15b-octahydrowhich the starting material 3H-benzo[6.7]cyclohepta[1,2,3-

starting delpyridol'2,1-a1isoquinolinaminoketone -01] is prepared 275 186 cH Mgl 3,3,4,5.6.6-hexamethyl- 276 185 CH =CHMgBr 3,3.4,6,-pentamethyl-S-vinyl- 277 186 HC I CLi S-ethynyl-3,3,4,6.6-pentamethyl- 278 186 (CH HLi S-cyclopentyl-3,3,4.6,6-pentamethyl 279 187 iC,-,H Li 4-sec-butyl-5-isopropyl- 280 187 HC I CLi 4-sec-butyl-5-ethynyl- 281 187 (C HLi 4-sec-butyl-5-cyclopropyll" 1 282 187 (CIEQ)ZF(CH3)LI* 4-sec-butyl-5-( l-methylcyclopropyl)- 283 188 CH,==CHLi 3,4-dimethyl-5-vinyl- 284 188 HC I CLi 5-ethynyl-3.4-dimethyl- 285 188 (C HLi 5-cyclopropyl-3.4-dimethyl- 286 188 (CH,),C(CH;,)Li* 3,4-dimethyl-5-( l-methylcyclopropyl)- 287 171 (CH,);,CHLi S-cyclobutyl- 288 171 (CH,) (n--C;,l-l-,)Li" 5-(1-propylcyclopropyl)- 289 171 (Cl-1 );.C(C H,-,)Li* S-(1-ethy1cyclobuty1)- 290 171 (CH,) C(CH )Li* 5-(1-methylcyclopentyl)- 291 171 (CH ),,C(CH; )Li* 5-(1-rnethy1cyc1ohexyl)- 292 171 (CH C(CH )Li* S-(1-methylcyclopropyl)- Prepared from the corresponding bromide derivatives according to the method of R. G. Jones and H. Gilman, Organic Reactions, 6, 352 (I951). The corresponding cyclobutyl, cyclopentyl and cyclohexyl bromides are prepared by the method of J. G. Traynham and O. S. Pascual, J. Org. Chem., 21, 1362 (1956); the corresponding cyclopropyl bromides are prepared by the method of B. C. Anderson, J. Org. Chem. 27. 2720 (1962) using methallyl chloride, Z-methylbutenyl chloride [H. Hoberg, Annalen der Chemie, 656, l (1962)] and 2-methylpent-2-enyl chloride [M. B. Evans et al., J. Chem. 800., 5045 (1962)] as starting materials for the l-methyl-l-ethyland l-propylcyclopropyl bromides, respectively.

EXAMPLE 293 A mixture of 5-ethyl-l,4,5,6,6a,10,11,15boctahydro-3 H-benzo[ 6,7 ]cyclohepta[ 1,2,3- de]pyrido[2,1-a]isoquinolin-5-ol (isomer A) (1.5g), described in Example 189 and anhydrous sodium acetate (0.6g) in acetic anhydride is heated at 130C for 16 hrs. The reaction mixture is cooled, diluted with benzene and water. The benzene layer is separated, washed with sodium carbonate solution and'waterand then dried over magnesium sulfate. Concentration of used in Example 293. For example, S-ethyl- 1,4,5,6,6a,10,11,15b-octahydro-3H benz0[6,7]cyclohepta[ l,2,3-de]pyrido[2.lalisoquinolin-S-ol heptanoate, 'y fi 1731 cm,

may be obtained by replacing acetic anhydride with an equivalent amount of heptanoic anhydride in the procedure of Example 293. Again, for example, S-t-butyl- 1,4,5,6,6a,10,11,15b-octahydro-3H- benzo[6,7lcycl0hepta[1,2,3de]pyrido[2,1- a]isoquinolin-5-ol acetate (lsomer A), nmr(CDCl 2.12( s,3H)4.86(t, 1H), may be obtained by replacing the benzene extract afford S-ethyl- 5-ethyl-1,4,5,6,6a,10,11,15boctahydro-3H- 1,4,5,6,6a,10,11,15b-octahydr0-3H- benz0[6,7]cyclohepta[1,2,3-de]pyrid0[2,lbenz0[6,7]cyclohepta[l,2,3-de]pyrido[2,1- a]isoquinolin-5-ol with an equivalent amount of the alisoquinolin-S-ol acetate as an oil, 'y ff 1735 corresponding S-t-butyl analog (Isomer A), prepared cm. The corresponding hydrochloric acid addition as described in Example 190, in the procedure of Example 293. The hydrochloric acid addition salt of -tbutyl-1,4,5,6,6a,l0,l l,l5b-octahydro-3I-I- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,la]isoquinolin-S-ol acetate (Isomer A) has m.p. 228--229C.

EXAMPLE 294 collected yielding 1 ,3,4,6,6a,10,1 1,15b-octahydro-5I-I- benzo[6,7]cyclohepta[ 1 ,2,3-de]pyrido[2,1-

and the reaction mixture is refluxed for six hours. After decanting and concentrating to a minimum volume, it is poured on water and extracted with ether, dried and concentrated to an oil. This oil is dissolved in ether and treated with gaseous hydrochloric acid. The resulting precipitate is recrystallized from isopropanol-acetone to yield a product identical with l,4,5.6,6a,l0,1 1,15boctahydro-3H-benzo[6,7]cyclohepta[1,2,3- de]pyrido[2,1-a]isoquinoline (Isomer A) hydrochloride described in Example 85.

The procedure of Example 295 may be followed to prepare other benzocycloheptaisoquinolines of formula I listed in Table XI. In each case an equivalent amount of the appropriate thioketal of the aminoketones listed in Table VII, prepared according to the procedure described in Example 294, is used as the thioketal starting material instead of l,3,4,6,6a,10,l 1,15- b-octahydro 5H-benzo[6,7]cyclohepta[1,2,3-de]- pyrido[2,l-isoquinolin-S-one ethylene dithioketal.

TABLE XI PRODUCT [(PREFIX LISTED BELOW)- l, .5.6.6a.l0,l l,l5b-OCTA- HYDRO-3H-BENZOI6J]CYCLO- HEPTAII,2.3-de]PYRlDO[2,l-a]- ISOQUINOLINE HYDROCHLORIDE] S-ONE ETHYLENE DITl-IIOKETAL] Z96 3-methyl- 3-methyl- 297 4-methyl- 4-methyl- 298 G-methyl- G-methyl- 299 3- ethyl- 3-ethyl- 300 4-ethyl- 4-ethyl- 301 6-ethyl 6-ethyl- 302 ,3-propyl- 3-propyl- 303 4-propyl- 4-propyl- 304 6-propyl- -propyl- 305 3,3-dimethyl- 3,3-dimethyl- 306 16,6-dimethyl- 6,6-dimethyl- 307 6,6-diethyl- 6,6-diethyl- 308 6-ethyl-3-methyl 6-ethyl-3-methyl- 309 3,3-dimethyl-6-propyl 3.3-dimethyl-6-propyl 310 3.3.4.6.6-pentamethyl- 3 ,3,4,6,6-pentamethyl- 31 I 4-sec-butyl- 4-sec-butyl- 312 3,4-dimethyl 3 ,d-dimethyla]isoquinolin-5-one ethylene dithioketal, m.p. EXAMPLE 313 220-225C.

If desired this product may be separated into its A and B isomers by chromatography on silica gel. The corresponding Isomer B has m.p. 150 after elution with chloroform and recrystallization from methanolhexane and the corresponding Isomer A, has m.p. 225230C after elution with methanol and recrystallization from methanol hexane.

The procedure of Example 294 may be followed to prepare the corresponding ethylene dithioketals of the other aminoketones of ketones of formula VIII of this invention, listed in Examples 172-188. In each case the appropriate aminoketone is used as starting material instead of l,3,4,6,6a,10,l 1,15b-octahydro-5H- benzo[6,7]cyclohepta[ l ,2,3-de]pyrido[2, I a]isoquinolin-5-one.

EXAMPLE 295 hydrofuran, Raney nickel 170 g) is added portionwise To a suspension of l,3,4,6,6a,10,11,15b-octahydro- 5H-benzo[6,7]cyclohepta[1,2,3-de[pyrido[2,1-

a]isoquinolin-S-one isomer A (2.0 g), described in Example 171, in 50 ml of methanol, sodium borohydride (2.5 g) is added portionwise. The mixture is heated under refluxing conditions for one hour. After removal of the methanol under vacuum, water is added and the mixture is extracted with ethyl acetate. The extract is dried, concentrated to dryness. The residue is crystallized from ether-hexane to afford the free base, 1,4,5 ,6- ,6a,l0,l 1,15b-octahydro-3I-I- benzo[6,7]cyclohepta[ I,2,3-de]pyrido[2,la]isoquinolin-S-ol, isomer A m.p. 157-159C. The corresponding hydrochloric acid addition salt of this free base has m.p. 290295C.

The corresponding acetic acid ester is prepared by reacting the above alcohol with acetic anhydride in presence of pyridine. The resulting S-acetoxyl,4,5,6,6a,10,11,15b-octahydro-3I-I- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,1-a]- isoquinoline is characterized by its nmr spectrum show- Using the isomer B of 1,3,4,6,6a,10,l1,15boctahydro-H-benzo[6,7]cyclohepta[1,2,3-de]- pyrido[2,l-a]isoquinolin-5-one described in Example 171, the corresponding alcohol B, m.p. l37140 is isolated. The hydrochloric acid addition salt of this free base melts at 280-285C.

These free bases may be converted to their corresponding tosylates or mesylates and reduced with lithium aluminum hydride or sodium amalgam, according to the methods described by Fieser and Fieser, cited above, pp. 292-294, see also 0. H. Wheeler in The Chemistry of the Carbonyl Group", cited above, to give a compound identical to 1,4,5,6,6a,l0,l 1,15boctahydro[ l,2,3-de]pyrido[2,1-a]isoquinoline (isomer A or isomer B, respectively) described in Example 85.

The procedure of Example 313 may be followed to I prepare the products listed in Table XI, for example, the product of Example 31 1. In each case the appropriate starting material, an aminoketone product listed in Table VII, for example, the product of Example 187, is reduced to the corresponding 5-alcohol, for example, 4-sec-butyl-l,4,5,6,6a,10,1 1,15b-octahydro-3H- benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1--' a]isoquinolin-5-ol[nmr 8 (CDCI 4.52(d,lH); the corresponding hydrochloric acid addition salt has m.p. 272280C.], converted to its corresponding tosylate or mesylate, and reduced again according to the above procedure.

The procedure of the first part of Example 313 may be followed to prepare other 5-alcohols listed in Table XII, instead of 1,4,5,6,6a,10,1 1,15b-octahydro-3H- benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,lalisoquinolin-S-ol. In each case an equivalent amount of appropriate starting material, an aminoketone product listed in Table VII is reduced with sodium borohydride to yield the corresponding 5-alcohol as product, as shown in the following Table XII.

TABLE XII EXAMPLE 331 5-Ethyl-1,4,5,6,6a,10,1 1,15b-octahydro-3H- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,la]isoquin0lin-5-ol (Isomer A), described in Example 189, may be dehydrated according to the conditions described by R. B. Wagner and H. D. look, in Synthetic Organic Chemistry, John Wiley and Sons, New York, 1953, pp. 32-35, preferably with p-toluenesulphonic acid in benzene solution, followed by hydrogenation according to the conditions described in above Example 84, to give 5-ethyl-1,4,5,6,6a,10,l 1,15boctahydro-3H-benzo[6,7]cyclohepta[ 1,2,3- de]pyrido[2,1-a]isoquinoline, A,,,,, 263 my. (5 582) and 270 my. (a 490).

The procedure of Example 331 may be followed to prepare S-methyland 5-propyl-l,4,5,6,6a,l0,11,15boctahydro-3H-benezo[6,7]cyclohepta[1,2,3- de]pyrido[2,l-alisoquinoline. In each case the S-ethyl- 1,4,5,6,6a, l 0,1 1,15b-octahydro-3H- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,1-a]- isoquinolin-S-ol is replaced by an equivalent amount of the S-methyl analog, described in Example 196, or the 5-propyl analog, described in Example 199, respectively.

Also, the procedures of Example 189 and 331 may be followed in sequence to prepare the 5-methy-l-, S-ethyland 5-propylderivatives of the aminoketone products listed in Table XI. In each case the appropriate starting material, an aminoketone product listed in Table VII, is reacted with methyl, ethyl or propyl magnesium bromide, respectively, and the resulting free base containing a hydroxyl group is dehydrated and hydrogenated according to the above procedure.

We claim:

1. A compound of the formula EXAMPLE STARTING MATERIAL [(PREFIX LISTED BELOW 1,3.4,6,6a,10,l1,15b- OCTAHYDRO-SH- BENZO[6,7]- CYCLOHEPTA[1,2,3-de]- PYRIDO[2,1-a]lSOQUlNOLlN- lSOQUINOLIN-S-OL CORRESPONDING S-ALCOHOL PRODUCT [(PREFIX LISTED BELOW 1,4,5,6,6a,10,1 1,1 Sb-OCTA- HYDRO-3I-IBENZO[6.7]CYCLO- o n H NH-C- AlR-Y- wherein Alk represents S-yl )methyl l-5-chlorovaleramide. 

1. A COMPOUND OF THE FORMULA
 2. N-((10,11-Dihydro-5H-dibenzo(a,d)cyclohepten-5-yl)methyl)-4-hydroxy -butyramide.
 3. N-((10,11-Dihydro-5H-dibenzo(a,d)cyclohepten-5-yl)methyl)-4-hydroxy -valeramide.
 4. N-(10,11-Dihydro-5H-dibenzo(a,d)cyclohepten-5-yl)methyl)-5 -hydroxyvaleramide.
 5. N-((10,11-Dihydro-5H-dibenzo(a,d)cyclohepten-5-yl)methyl)-5 -chlorovaleramide. 